Activity of interleukin-2 in non-Hodgkin's lymphoma following transplantation of interleukin-2-activated autologous bone marrow or stem cells.
OBJECTIVE
Disease recurrence constitutes the major cause of treatment failure following autologous transplantation for non-Hodgkin's lymphoma (NHL). Preclinical models indicate that bone marrow or stem cells that have been exposed to recombinant interleukin-2 (rIL-2) can be immunologically purged of chemotherapy-resistant malignant cells while retaining their proliferative potential. Continued treatment with rIL-2 in the posttransplantation period may further enhance the antitumor effect. We review here a phase I clinical study conducted to address the feasibility of this immunotherapeutic approach for reducing the relapse rate following autologous transplantation.


METHODS
We have performed a phase I clinical trial of rIL-2-treated autologous bone marrow or stem cell transplantation for patients who had hematologic malignancies with poor prognoses. Conditioning for lymphoma patients consisted of thiotepa (250 mg/m2/day x 3 days), busulfan (1 mg/kg orally every 6 hours for 3 days), and cyclophosphamide (60 mg/kg/day x 2 days). Autologous bone marrow or granulocyte colony-stimulating factor (G-CSF) -mobilized autologous stem cells were thawed and exposed for 24 hours to rIL-2 (6000 IU/mL). Posttransplantation rIL-2 therapy (1-2 MIU/m2/day) was administered by continuous infusion from day 1 for a minimum of 21 days. Subsequently, all patients were to receive six cycles of maintenance rIL-2 (6 MIU/m2/day) for 5 days per week in weeks 1 and 2 every 28 days. Patients also received G-CSF (5 micrograms/kg) from day 1 until neutrophil recovery. Twenty-eight patients were accrued, of whom 19 had recurrent or refractory NHL. The median age of NHL patients was 33 years (range, 17-48 years). Seventeen patients had intermediate-grade lymphoma and two had high-grade lymphoma. Five patients received bone marrow, 10 patients received peripheral blood stem cells (PBSC), and four patients received a combination of PBSC and bone marrow.


RESULTS
All patients engrafted. The median time to reach a granulocyte count of 0.5 x 10(9) cells/L was 11 days (range, 8-41 days). The median time to reach a platelet count of 50 x 10(9) cells/L was 34 days (range, 9-242 days). The most common dose-limiting toxicities associated with posttransplantation and maintenance rIL-2 therapy were fever, fatigue, and nausea. Among 19 NHL patients, eight patients have developed progressive disease and two patients have died from bilateral pneumonia or radiation-induced cardiomyopathy. Nine patients (47%) remain disease free with a median follow-up of 225 days (range, 150-948 days).


CONCLUSIONS
These data indicate the feasibility of transplanting rIL-2-activated bone marrow or stem cells followed by posttransplantation immunotherapy in patients with advanced NHL. The potential antitumor efficacy of this approach is undergoing further evaluation in a prospective phase II trial.
van Besien
K
K
Department of Hematology/Oncology, University of Illinois at Chicago 60612, USA.
Margolin
K
K
Champlin
R
R
Forman
S
S
D000328:Adult; D001853:Bone Marrow / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000379:methods*; D005240:Feasibility Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use*; D008228:Lymphoma, Non-Hodgkin / Q000401:mortality / Q000628:therapy*; D008875:Middle Aged; D010865:Pilot Projects; D013234:Stem Cells / Q000187:drug effects; D015996:Survival Rate
D007376:Interleukin-2